When a blood vessel is ruptured, the body immediately produces thrombin to avoid bleeding to death. On the other hand, an excess amount of thrombin produced due to an inflammatory reaction or the like in a damaged vessel causes thrombosis, leading to impairment of important organ functions. Therefore, for therapy or prophylaxis of thrombosis, a thrombin inhibitor such as heparin or warfarin, which inhibits thrombin production or directly inhibits the thrombin activity, has been used as an anticoagulant for a long time. However, the degree of medical satisfaction with these drugs is not necessarily high, and research and development on novel anticoagulants, having excellent dose-response relationships, a low risk of hemorrhage, and that can be orally administered, is now being pursued on a global scale.
The mechanisms of blood coagulation have been divided into the “intrinsic coagulation pathway”, which is initiated by activation of factor XII (FXII) due to contact with a negatively charged substance, and the “extrinsic coagulation pathway”, which is activated by tissue factor (TF) and factor VII (FVII). In the case of development of thrombosis, the extrinsic coagulation pathway has been suggested to be important since TF is specifically expressed in the pathological condition. Therefore, it has been thought that compounds that inhibit blood coagulation factor VIIa which is positioned furthest upstream in the extrinsic coagulation pathway are useful as therapeutic and/or prophylactic agents for diseases caused by thrombus formation, such as thrombosis in which the extrinsic coagulation pathway is involved.
Known examples of such compounds that inhibit blood coagulation factor VIIa include amidinonaphthol derivatives (see Non-patent Document 1), amidino derivatives (see Patent Document 1), N-sulfonyldipeptide derivatives (see Patent Document 2), 6-[[(allyl)oxy]methyl]naphthalene-2-carboxylmidamide derivatives (see Patent Document 3) and phenylglycine derivatives (see Patent Documents 4 and 5). Further, triazolone derivatives (see Patent Document 6), which are the active constituents of the prodrugs of the present invention, are known.
However, known compounds are insufficient with respect to their inhibitory activity against blood coagulation factor VIIa, anticoagulant action, therapeutic action against thrombosis, and the like. For triazolone derivatives, further improvement of absorbability upon oral administration has been considered necessary.